Cancer continues to be one of the foremost health problems. Conventional treatments such as surgery, chemotherapy and radiation therapy have exhibited favorable results in many cases, while failing to be completely satisfactory and effective in all instances. For example, the effectiveness of orthodox radiation therapy on deep pulmonary, bronchial, and esophageal tumors is limited by the risk of radiation pneumonitis.
The goal of radiation therapy is generally to maximize the therapeutic index, which is defined as the ratio of the maximum tolerable dose beyond which unacceptable levels of normal tissue toxicity would occur, to the minimal dose required for effective tumor control. This goal is particularly difficult to achieve in treating central nervous system (CNS) tumors. Malignant gliomas which include astrocytomas, oligodendrogliomas and glioblastoma represent about 60% of all primary brain tumors, with an incidence of over 8,000 cases per year. The survival statistics of patients with high grade gliomas in the brain, or lower grade gliomas and metastatic tumors in the spinal cord have not improved appreciably in recent years using conventional surgical techniques and conventional radiotherapy. The doses that can be delivered to malignant CNS tumors are limited by the tolerance of normal brain and spinal cord to radiation. For higher grade CNS tumors, radiation is generally offered only as a palliative rather than curative therapy. For lower grade CNS tumors, the ratio of radiotherapy doses that produce normal CNS toxicity and those that control the tumor is so close that it often renders radiotherapy ineffective, or results in neurological complications from radiotoxicity to the normal CNS surrounding the tumor. In addition, tolerance of the normal CNS to re-treatment, if necessary, will be lower.
It is well known to those skilled in the art that the threshold dose, or maximum tolerable dose before neurological and other complications of radiotherapy arise, increases as irradiated volumes of tissue are made smaller. Such observations eventually led to the development of grid radiotherapy using grids or sieves for spatial fractionation of X-rays. Recently, a much less familiar alternative form of radiation therapy, known as microbeam radiation therapy (MRT), has been investigated to treat tumors such as these for which the conventional methods are ineffective or associated with a high risk factor.
The concept of MRT was introduced in U.S. Pat. No. 5,339,347 to Slatkin et al. MRT differs from conventional radiation therapy by employing arrays of parallel planes of radiation, which are at least one order of magnitude smaller in thickness (or diameter if, in the rare case, parallel cylindrical beams are used rather than planar beams) than the smallest radiation beams in current conventional clinical use. These very thin microbeams, which are also called microplanar beams, can be generated using the high intensity X-ray beams that are currently generated at electron synchrotron storage rings.
The optimum thickness of the individual microbeams used in the array is dependent upon the capacity of tissue surrounding a beam path to support the recovery of the tissue injured by the beam. It has been postulated that segments of the capillary blood vessels destroyed in the direct paths of the individual microbeams are replaced by the microvasculature regeneration effected by the capillary segments surviving between individual microbeams.
For example, normal rat-brain tissues have been shown to display an unusually high resistance to damage when irradiated with such beams, if the individual microbeams of tens of micrometers in thickness are delivered at skin-entrance absorbed doses of up to about 5000 Gy. Also, arrays of microbeams with 20–90 micrometers (μm) of beam width and about 100–300 μm of center-to-center spacing of adjacent beams are tolerated up to 625 Gy of in-beam incident doses. This sparing effect has been attributed to rapid repair of microscopic lesions by unirradiated adjacent cells in the capillary blood system and the glial system. Because of this high resistance of normal brain tissues to very high radiation doses, multiple parallel microplanar beams of uniform microscopic thickness (in the range of tens of micrometers) and macroscopic breadth or width (in the centimeter range) have been proposed for treating brain tumors in human infants, for example, in Slatkin et al., “Subacute Neuropathological Effects of Microplanar Beams of X-rays from a Synchrotron Wiggler,” Proc. Natl. Acad. Sci. USA, Vol. 92, pp. 8783–8787 (1995b), which is incorporated herein by reference.
The Slatkin et al. patent discloses the segmentation of a broad beam of high energy X-ray into microbeams (beams of thickness less than about 1 millimeter (mm)), and a method of using the microbeams to perform radiation therapy. The target tissue, e.g., a tumor, receives a summed absorbed dose of radiation exceeding a maximum absorbed dose tolerable by the target tissue by crossing or intersecting microbeams at the target tissue. The irradiated in-path non-target tissue is exposed only to non-crossing beams. Non-target tissue between the microbeams receives a summed absorbed dose of radiation less than the maximum tolerable dose, i.e., a non-lethal dose to non-target tissue. In this way, the irradiated non-target tissue in the path of the microbeam is allowed to recover from any radiation injury by regeneration from the supportive cells surviving between microbeams. The probability of radiation-induced coagulative necrosis in the irradiated normal, non-targeted tissue is also lowered due to the non-crossing beam geometry in the non-target tissue, allowing for lower levels of radiation to the non-target tissue. Using microbeam radiation therapy in this way helps improve the effectiveness of clinical radiation therapy, especially for deep-seated tumors.
The microbeams geometries disclosed in the Slatkin et al. patent are of two basic types. Exposure of the target may be accomplished by a unidirectional array of microbeams which may be parallel or may converge at the target. Alternatively, two arrays of microbeams originating from different directions may be “cross-fired,” and intersect at an isocenter in the target tissue. The microbeams within each array may be substantially parallel to each other or may converge at an isocenter within the target.
Radiation-enhancing agents have been used experimentally in radiation therapy. For example, radiation sensitizers which use pharmaceutical compounds with gadolinium in them, such as motexafin gadolinium (MGd), have been used to enhance the radiation damage to the target tissue by increasing the amount of free radicals produced by the radiation. These sensitizers, however, are commonly highly toxic, and care must be taken not to administer too large of a quantity of these compounds to a subject. Even with careful administration, an unwanted risk to the subject is imposed by this method, because of variations in tolerance levels among subjects.
In a similar way, contrast agents have been used in experimental conventional radiation therapy in a type of phototherapy commonly called photon activation therapy. Photon activation therapy typically includes two steps: accumulation of a substance of high atomic number within the target tissue and localized activation of the substance with an appropriately tuned monochromatic photon source. In the absence of activation, the substance, referred to herein as an activating substance or an activating radiation enhancer, is preferably non-toxic. In addition, the required irradiation dose to activate the substance should be below the minimum absorbed dose which would be lethal to non-target tissue minimally containing the activating substance. Only the combination of both the accumulation of the substance in the target tissue and direct irradiation of the target tissue with the monochromatic source, therefore, leads to the desired synergistic effect of ablating the targeted tumor.
Typically, a monochromatic X-ray beam is tuned to just above (or slightly more above) the so-called K-edge energy of the substance, for high absorption of tissue containing the activating radiation enhancer. The substances conventionally used are imaging contrast agents known to be highly absorbing of the incident monochromatic beam. In one example, iodine is a known activating substance which can be injected intravenously into a subject and used in photon activation therapy to treat a brain tumor. Due to blood brain barrier breakdown, the iodine preferentially accumulates in the tumor. The monochromatic X-ray beam is tuned to be above the K-edge of iodine (just above or shortly above it), which is about 33.2 keV, and directed at the site of the tumor, in a dose not exceeding normal tissue tolerance (in the absence of activation).
The dose and the concentration of iodine in the tumor is typically adjusted such that minimal damage is sustained by normal tissue in the path of a conventional X-ray broad beam, while an enhanced therapeutic dose is delivered at the site of the tumor because of the highly absorbing effect of the contrast agent. In practice, however, there is still the risk of radiation-induced tissue necrosis by the broad X-ray beam.
Experiments have been performed to combine use of the radiation enhancer motexafin gadolinium (MGd) for photon activation therapy with cross-planar microbeam radiation therapy to provide crossing beams and thus to further enhance the X-ray dose only at the site of the target tumor, as described in Zhong, et al., “Evaluation of the Radiation Enhancer, Motexafin Gadolinium (MGd), for Microbeam Radiation Therapy of Subcutaneous Mouse EMT-6,” National Synchrotron Light Source Activity Report (2001) Abstract No. zhon193. The MGd compound was used in these experiments for its chemical properties as an enhancer of free radicals in tissue. It is extremely toxic, however, and has a very small amount of gadolinium in it. Therefore, only a small amount can be administered to the subject.
There is a need in the prior art, therefore, for more efficient methods of radiation therapy which greatly enhance the therapeutic dose at the tumor, while simultaneously maintaining a safe dose to normal tissue.